Clinical pathological correlations for human genetic disorders affecting the nervous system are important for the logical and successful development of diagnostic techniques and therapeutic strategies. These goals are also facilitated by a comprehensive knowledge of the biochemistry and clinical heterogeneity of these disorders. Gaucher disease, the most common sphingolipidoeis, is extremely useful as a model because of the occurrence of both neuronopathic and non-neuronopathic phenotypes. Understanding the basis of the broad spectrum of clinical diversity within the major types of this disorder may provide insight into factors which contribute to phenotypic heterogeneity in other diseases. Phenotypic heterogeneity in Gaucher disease is studied both through clinical examination of diverse patient populations and by study of transgenic animal models created by gene targeting. The gaucher mouse homozygous for null alleles has a devastating clinical course. It has aided in the recognition of a subgroup of type 2 Gaucher patients who die in the neonatal period. Both the Gaucher mice and neonatal patients have skin changes, substantiating the important role of glucocerebrosidase in the maturation of functionally normal skin. The generation of other less severely affected Gaucher mice by gene targeting of specific point mutations should also provide valuable insights into the human disease. Studies are ongoing to attempt to correlate patient phenotype with DNA mutation, but in Gaucher disease there is significant genotypic heterogeneity among clinically similar patient., and it is thus still difficult to assign a clinical prognosis based solely upon PCR determined genotype. Other factors including transcription regulatory regions activator proteins and the role of the nearby gene sequences, such as a pseudogene, are being studied. The techniques and information obtained from the study of heterogeneity and gene expression in Gaucher disease should be useful for formulating strategies for recognizing and understanding the biochemical and genetic bases of other disorders affecting the nervous system.